Heart failure due to heart disease is a major health concern and a leading cause of mortality worldwide. Despite improvements in treatment options, repair of damaged myocardial tissue is still a central therapeutic challenge in cardiovascular regenerative medicine. Currently, bone marrow derived endothelial progenitor cells (BM-EPCs) are being used clinically to improve vascularization in patients with ischemic heart disease. The therapeutic benefits of BM-EPC therapy in animal models have been attributed to paracrine factors-mediated vascular repair without myogenesis and/or myocardial regeneration. Therefore, the long-term goal of this proposal is to improve the cardiomyogenic properties of an existing autologous cell therapy approved for the clinic. This proposal focuses on epigenetically modifying endothelial cells to create multipotent cells capable of repairing cardiac tissue after an acute myocardial infarction. Endothelial cells and cardiomyocytes both differentiate from a common progenitor in the mesoderm, suggesting that reprogramming endothelial cells back to that early state in mesoderm development could recapitulate their cardiomyogenic potential. Epigenetic reprogramming using chemical modifiers of DNA methylation (5-Azacytidine) and histone acetylation (valproic acid) have been shown to change the trans-differentiation capabilities of a given cell. For instance, mesenchymal stem cells (MSC) treated with 5'Azacytidine have an increase in cardiomyocyte differentiation and they improve cardiac function upon transplantation compared to control MSCs. In our preliminary experiments we find: a.) treatment of endothelial progenitor cells with epigenetic modifiers induces the expression of non-endothelial specific genes, while b.) endothelial-specific gene expression is maintained, c.) reprogrammed cells can be re-differentiated into cardiomyocytes under proper in vitro conditions and d.) epigenetically modified endothelial progenitor cells are therapeutically superior in the myocardial infarction model to non-treated cells. Therefore, we hypothesize that epigenetic modifying agents can reprogram endothelial cells to a multipotent state, capable of regenerating and/or repairing injured myocardium in vivo by differentiating into both cardiomyocytes and endothelial cells. PUBLIC HEALTH RELEVANCE: Heart disease is a leading cause of morbidity and mortality amongst Americans. Our studies, if successful, will generate a novel set of well-controlled experimental evidence supporting the increased potential for regeneration of the heart when endothelial progenitor cells are treated with 5'Azacytidine, Trichostatin A and valproic acid. Most importantly, our results may significantly improve an existing cellular therapy and improve the lives of the over 16 million patients in the United States living with coronary heart disease.